Project Summary: Highly potent antiretroviral medications have greatly prolonged the lives of patients infected with the human immunodeficiency virus (HIV). However, the use of these medications is associated with development of a syndrome consisting of abnormal changes in fat distribution, dyslipidemia, and abnormal glucose homeostasis. These abnormalities increase the risk of diabetes and cardiovascular disease. Subcutaneous lipoatrophy is a common complication of antiretrovirals. Lipoatrophy is an independent risk factor for insulin resistance and dyslipidemia, and causes significant psychological distress. Trials to increase subcutaneous adiposity and reverse the medical complications of the syndrome have had mixed results. Insulin like growth factor-l (IGF-I) increases insulin sensitivity, and because it prevents cell death, might also reduce loss of fat tissue. The purpose of this study is to test the efficacy of recombinant IGF-I in the treatment of HIV associated lipodystrophy syndrome. The specific aims are to (1) Determine the effect of recombinant IGF-I on subcutaneous adiposity in patients with HIV lipodystrophy syndrome;(2) determine the effects of IGF-I on lipids and glucose homeostasis;and (3) examine the role of IGF-I activity in mediating the fat distribution changes and metabolic problems of the syndrome. Forty-eight patients will be randomized to either placebo or recombinant IGF-I, in double-masked fashion. Patients will be assessed at baseline and after 24 weeks of treatment. After 24 weeks, all patients will be given active therapy until week 48. Assessments includes blood samples to measure glucose, insulin, and lipoproteins;adipose tissue biopsy at 0 and 24 weeks;and body composition assessment at 0, 24 weeks, and 48 weeks, using dual energy x-ray absorptiometry and computed tomography. Patients will also undergo the hyperinsulinemic clamp at week 0 and again at week 24. Adipose tissue will be analyzed for changes in apoptosis and mitochondrial toxicity. In vitro experiments will be conducted to characterize how antiretrovirals inhibit normal activity of IGF-I signaling and the interrelationship of this pathway to adipocyte apoptosis. PUBLIC HEALTH RELEVANCE: This study could indicate a new strategy for treating a common and difficult problem in HIV care, one which may increase in frequency globally. The study may also increase our understanding of the role of the IGF-I hormone in regulating the amount and biological properties of human fat tissue. This could help us understand other medical conditions such as diabetes and obesity.